As a research assistant professor in the laboratory of Dr. John Crispino, I lead a major effort to develop novel therapies for patients with blood cancers, I assist other lab members in their translational initiatives, and I collaborate with external colleagues to enhance their cancer research. The main area of my research involves the investigation of the pathogenesis of acute megakaryocytic leukemia (AMKL), and the role of megakaryocytes in the development of other blood cancers, such as primary myelofibrosis (PMF), which is a subtype of the myeloproliferative neoplasms (MPNs). During normal development, megakaryocytes progress through repeated rounds of the cell cycle without cell division to become polyploid. I hypothesized that small molecules that could force malignant megakaryocytes to become polyploid and differentiate would act as anti- tumor agents. Indeed, I discovered that megakaryocytic polyploidy inducing molecules such as dimethylfasudil and MLN8237 (Alisertib), which inhibit Aurora A kinase, have potent anti-AMKL activity in vitro and in vivo. Moreover, these compounds showed strong anti-tumor activity in patient samples and mouse models of PMF. These findings lead to the opening of a Phase 1 clinical trial of Alisertib in patients with AMKL or PMF. From this study I accumulated an enormous amount of experience in drug development from the design of high throughput small molecule and RNAi screens to preclinical studies with animal models. Over the next five years, I will leverage my experience to further my own research as well as to aid lab colleagues in their studies to find new therapies for hematologic malignancies. My work can be divided into four focus areas: A) development of therapies for megakaryocytic malignancies; B) validation of PAK1 as a target in the MPNs; C) development of DYRK1A inhibitors for AMKL and B-ALL; D) investigation of novel therapies to target cohesin mutations in AMKL and AML. I look forward to continuing to be an instrumental leader in Dr. Crispino's lab, to collaborating with other NCI-funded investigators, and to bringing more novel therapeutics to patients.

Public Health Relevance

My passion is to perform cutting edge research in hematology/oncology with the goal of translating my discoveries into new therapies for patients. I led an international effort to identify drugs that induce the polyploidization of malignant megakaryocytes, which has culminated in the opening of a Phase 1 study of an aurora A kinase inhibitor in acute megakaryocytic leukemia and primary myelofibrosis. Over the next five years I will continue to study megakaryocytic blood cancers as well as support the translational cancer research of colleagues in my laboratory as well as those of external collaborators.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Project #
5R50CA211534-04
Application #
9762040
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Duglas Tabor, Yvonne
Project Start
2016-09-19
Project End
2021-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Zhao, Baobing; Mei, Yang; Cao, Lan et al. (2018) Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms. J Clin Invest 128:125-140
Gilles, Laure; Arslan, Ahmet Dirim; Marinaccio, Christian et al. (2017) Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. J Clin Invest 127:1316-1320
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